ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3708T>G (p.Asn1236Lys) (rs28897687)

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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000083197 SCV001161511 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 6.81E-11
Invitae RCV000048292 SCV000076305 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
GeneDx RCV000120300 SCV000108670 likely benign not specified 2018-02-20 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000131695 SCV000186731 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CSER _CC_NCGL, University of Washington RCV000148395 SCV000190094 likely benign Breast and/or ovarian cancer 2014-06-01 criteria provided, single submitter research
Michigan Medical Genetics Laboratories,University of Michigan RCV000083197 SCV000195924 likely benign Breast-ovarian cancer, familial 1 2015-04-22 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000120300 SCV000219233 uncertain significance not specified 2017-03-01 criteria provided, single submitter clinical testing
Vantari Genetics RCV000131695 SCV000267005 benign Hereditary cancer-predisposing syndrome 2015-11-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048292 SCV000494417 benign Hereditary breast and ovarian cancer syndrome 2015-11-23 criteria provided, single submitter clinical testing Variant Summary: The BRCA1 c.3708T>G variant affects a non-conserved nucleotide, resulting in amino acid change from Asn to Lys. 3/4 in-silico tools predict this variant to be benign. The composite observed allele frequency in controls, including the large and diverse ExAC cohort, is 29/121594 (1/4193); and the observed allele frequency in the Latino sub-population from ExAC population is 11/11570 (1/1052). These frequencies are not significantly different than the maximal expected allele frequency for a pathogenic BRCA1 variant (1/1000). However, the low frequency in control populations should still suggest that this variant is a rare polymorphism unless proven other. The variant has been cited to co-occur with various pathogenic BRCA1 and BRCA2 variants, including BRCA1 c.6944_6947delTAAA (p.Ile2315_Lys2316?fs), BRCA1 c.2722G>T (p.Glu908Ter), and BRCA2 c.8537_8538delAG (p.Glu2846Glyfs) from BIC and BRCA2 c.1310_1313delAAGA (p.Lys437IlefsX22) from UMD. These co-occurrence findings are a clear evidence that this variant is benign. Although the variant has been reported in multiple patients in the literature, the publications did not comprehensively rule out the presence of large rearrangements. LOH studies demonstrated the retention of wild type allele and the loss of the allele harboring this variant in tumors from 2 patients, further supporting a benign outcome (Osorio et al, 2002). In addition, a cell growth assay to measure this variant's ability to functionally complement BRCA1-deficient mouse embryonic stem cells showed the variant behaves like wildtype (Bouwman et al, 2013). Although clinical laboratories and databases are mixed in their classifications, the majority classify the variant as benign/likely benign/neutral. Taken together, this variant has been classified as benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000120300 SCV000538452 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 4 B/LB, 3 VUS
Department of Pathology and Molecular Medicine,Queen's University RCV000120300 SCV000588047 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120300 SCV000593670 likely benign not specified 2017-05-03 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000083197 SCV000743404 likely benign Breast-ovarian cancer, familial 1 2017-07-28 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000083197 SCV000744629 likely benign Breast-ovarian cancer, familial 1 2017-05-31 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679692 SCV000806939 likely benign not provided 2017-07-06 criteria provided, single submitter clinical testing
Mendelics RCV000048292 SCV000839248 likely benign Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory,Nationwide Children's Hospital RCV000120300 SCV000864296 likely benign not specified 2017-10-24 criteria provided, single submitter clinical testing BP1, BP4, BP6; This alteration is a missense alteration in a gene for which primarily truncating variants are known to cause disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory).
Color Health, Inc RCV000131695 SCV000902607 benign Hereditary cancer-predisposing syndrome 2015-08-13 criteria provided, single submitter clinical testing
Mendelics RCV000083197 SCV001140546 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283527 SCV001156768 likely benign none provided 2020-03-20 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000148395 SCV001333183 likely benign Breast and/or ovarian cancer 2018-07-12 criteria provided, single submitter clinical testing
ITMI RCV000120300 SCV000084452 not provided not specified 2013-09-19 no assertion provided reference population
Sharing Clinical Reports Project (SCRP) RCV000083197 SCV000115271 benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083197 SCV000144842 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Medical Genetics, University Hospital of North Norway RCV000083197 SCV000301434 uncertain significance Breast-ovarian cancer, familial 1 2016-05-01 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000120300 SCV000587335 not provided not specified 2014-01-31 no assertion provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353574 SCV000591464 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Asn1236Lys variant has been previously reported in the literature in 11 of 5896 proband chromosomes with hereditary breast and ovarian cancer and was identified in 3 of 1510 control chromosomes included in these studies (Borg 2010, Diez 2003, Lara 2012, Osorio 2007, Simard 2007, Spurdle 2008, Weber 2006). The variant was also identified in dbSNP (ID: rs28897687), the GeneInsight COGR database (classified as with unknown significance by four clinical labs, and as likely benign by one clinical lab), ARUP Laboratories BRCA database (classified with uncertain significance), BIC database (35x with uncertain significance), LOVD, the ClinVar database (classified as having “uncertain significance” by three submitters; as “likely benign” by one submitter; and as “benign” by three submitters). The variant was also in 39 samples submitted to UMD, where it was classified as “neutral”. One of these samples had a co-occurring pathogenic BRCA2 variant (c.1310_1313delAAGA, p.Lys437IlefsX22), increasing the likelihood that the p.Asn1236Lys variant may not have clinical significance. In addition, the variant was identified at polymorphic frequencies in three HapMap populations: Han Chinese in Beijing (freq: 0.026), Japanese in Tokyo (freq: 0.012), and Toscans in Italy (freq: 0.011). The variant is not conserved in all mammals, and the variant amino acid Lys is present in purple sea urchin, increasing the likelihood that this amino acid position may not be functionally important. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. A study using a multifactorial-likelihood ratio model (co-occurrence, pathology and conservation) yielded inconclusive results for the classification of this variant (Spurdle 2008). One functional study found that the variant did not affect BRCA1 interstrand crosslink repair (Bouwman 2013), and another study using a minigene assay found that the variant did not affect normal splicing of the BRCA1 gene (Anczuków 2008 in Walker 2013). In addition, loss of heterozygosity analysis of tumours in two patients showed retention of the wild-type allele and loss of the allele in which the variant was located, confirming that the variant was not deleterious (Osorio 2002). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000083197 SCV000733622 likely benign Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing

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